Comparison of biochemical cartilage imaging techniques at 3 T MRI.

OBJECTIVE: To prospectively compare chemical-exchange saturation-transfer (CEST) with delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and T2 mapping to assess the biochemical cartilage properties of the knee. METHOD: Sixty-nine subjects were prospectively included (median age, 42 years; male/female = 32/37) in three cohorts: 10 healthy volunteers, 40 patients with clinically suspected cartilage lesions, and 19 patients about 1 year after microfracture therapy. T2 mapping, dGEMRIC, and CEST were performed at a 3 T MRI unit using a 15-channel knee coil. Parameter maps were evaluated using region-of-interest analysis of healthy cartilage, areas of chondromalacia and repair tissue. Differentiation of damaged from healthy cartilage was assessed using receiver-operating characteristic (ROC) analysis. RESULTS: Chondromalacia grade 2-3 had significantly higher CEST values (P = 0.001), lower dGEMRIC (T1-) values (P < 0.001) and higher T2 values (P < 0.001) when compared to the normal appearing cartilage. dGEMRIC and T2 mapping correlated moderately negative (Spearman coefficient r = -0.56, P = 0.0018) and T2 mapping and CEST moderately positive (r = 0.5, P = 0.007), while dGEMRIC and CEST did not significantly correlate (r = -0.311, P = 0.07). The repair tissue revealed lower dGEMRIC values (P < 0.001) and higher CEST values (P < 0.001) with a significant negative correlation (r = -0.589, P = 0.01), whereas T2 values were not different (P = 0.54). In healthy volunteers' cartilage, CEST and dGEMRIC showed moderate positive correlation (r = 0.56), however not reaching significance (P = 0.09). ROC-analysis demonstrated non-significant differences of T2 mapping vs CEST (P = 0.14), CEST vs dGEMRIC (P = 0.89), and T2 mapping vs dGEMRIC (P = 0.12). CONCLUSION: CEST is able to detect normal and damaged cartilage and is non-inferior in distinguishing both when compared to dGEMRIC and T2 mapping.

Drug monitoring detects under- and overdosing in patients receiving 5-fluorouracil-containing chemotherapy-results of a prospective, multicenter German observational study.

INTRODUCTION: Body surface area (BSA)-based dosing of 5-fluorouracil (5-FU) results in marked inter-individual variability in drug levels, whereas determination of plasma 5-FU concentration and area under the curve (AUC) is a more precise dosing method but has not been integrated into clinical routine. We conducted a multicenter, prospective study to study 5-FU AUC distributions and assess clinical factors predicting therapeutic dosing in patients receiving BSA-dosed 5-FU. METHODS: Between June 2017 and January 2018, a total of 434 patients receiving continuous, infusional BSA-dosed 5-FU from 37 sites in Germany were included. Plasma 5-FU concentration and AUC were measured in venous blood samples at steady state. The primary objective was to determine 5-FU AUC distributions in relation to the target range, which is defined as 20-30 mg × h/l. The second objective was to explore clinical parameters that correlate with achievement of 5-FU AUC target range. RESULTS: The primary tumor was mainly located in the gastrointestinal tract (96.3%), with colorectal cancer being the most common (71.2%) tumor entity. 5-FU was administered as monotherapy (8.1%) or as part of FOLFOX (33.2%), FOLFIRI (26.3%), or other regimens (12.4%). Treatment setting was adjuvant (31.3%) or metastatic (64.5%). The median AUC was 16 mg × h/l. Only 20.3% of patients received 5-FU treatment within the target range, whereas the majority of patients (60.6%) were underdosed and 19.1% of patients were overdosed. In the univariate logistic regression, treatment setting was the only clinical parameter that significantly correlated with achievement of the target range. Patients treated in the metastatic setting had a 2.1 (95% confidence interval 1.186-3.776, P = 0.011) higher odds to reach the target range compared with patients treated in the adjuvant setting. CONCLUSIONS: The majority of patients received suboptimal doses of 5-FU using BSA dosing. Therapeutic drug monitoring of 5-FU is an option for optimized individualized cancer therapy and should be integrated into the clinical practice.

Capecitabine-associated hand-foot-skin reaction is an independent clinical predictor of improved survival in patients with colorectal cancer.

BACKGROUND: Hand-foot-skin reaction (HFSR) is an adverse event frequently observed during treatment with capecitabine (cape). In the present analysis, we sought to evaluate the potential association of HFSR and survival in German patients with metastatic colorectal cancer and locally advanced rectal cancer treated with cape in clinical trials. METHODS: Patients of the Arbeitsgemeinschaft für Internistische Onkologie (AIO) KRK-0104 and the Mannheim rectal cancer trial were evaluated. HFSR was graded according to NCI-CTC criteria in both trials. Time to first occurrence of HFSR was described per cycle and HFSR developing during cycles 1 and 2 was defined as 'early HFSR'. Baseline characteristics between the patient groups with or without HFSR were compared using Mann-Whitney-U, Fisher's exact or χ(2)-test, as appropriate. Haematological and non-haematological toxicities observed in both groups were compared using Fisher's exact test. Progression-free (PFS) or disease-free (DFS) as well as overall survival (OS) data from both trials were pooled and the HFSR group was compared with the non-HFSR using Kaplan-Meier analysis. RESULTS: A total of 374 patients were included, of whom 29.3% developed any HFSR. Of these, 51% had early HFSR. Baseline characteristics were comparable between both HFSR groups concerning age, gender, ECOG performance status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFSR. The percentage of all-grade (and grade 3-4) haematological toxicities did not differ between both the groups. By contrast, patients exhibiting HFSR had a significantly higher rate of all-grade (but not grade 3-4) diarrhoea, stomatitis/mucositis and fatigue (P<0.01, respectively). Patients with HFSR had improved PFS/DFS (29.0 vs 11.4 months; P=0.015, HR 0.69) and OS (75.8 vs 41.0 months; P=0.001, HR=0.56). Within the HFSR group, PFS/DFS and OS were comparable between patients with early vs late HFSR. INTERPRETATION: The present analysis provides evidence for the association of HFSR and survival in patients with colorectal cancer. Baseline characteristics, with the exception of UICC stage, older age and ECOG performance status, and the time of occurrence of HFSR had no impact on survival. Patients with HFSR had a higher probability of developing any-grade gastrointestinal toxicity and fatigue while no correlation with haematological toxicity was found.

[Compatibility of family and profession. Survey of radiologists and medical technical personnel in clinics with different organizations]. / Vereinbarkeit von Familie und Beruf. Umfrage unter Radiologen und medizinisch-technischen Angestellten in Kliniken unterschiedlicher Ausrichtung.

PURPOSE: The compatibility of family and profession is especially difficult for employees in medical professions because of shift work and overtime. It seems that in the future women are going to represent the majority of medical professionals in Germany. Hence, with the forthcoming lack of physicians in Germany social aspects will also play a greater role in the choice of the place of employment. Therefore a statistical survey was made among employees on how they judge the compatibility of family and job and what they would like to improve. MATERIALS AND METHODS: From autumn 2009 until spring 2010 a total of 115 questionnaires were distributed to 8 different academic radiology departments. The anonymous questionnaire with partially open, partially graded questions and partially multiple answer questions was designed with the help of an expert for statistics and analytics and included questions about the employment and family situation, plans for the future, requested flexible working hours and childcare models, as well as ideas for improvement. Of the questionnaires 87 were analyzed with a specially designed access database using, for example descriptive statistics and histogram analyses. RESULTS: Of the interviewees 68% were female and 31% were male (1% not significant n.s.), 46% had children and 49% were childless (5% n.s.), 63% were medical doctors, 33% radiographers (3% other) and 82% worked full-time. Of the male respondents with children 42% indicated that their spouse was at home, 18% of female respondents with children indicated that their spouse was at home and only mothers worked part-time. Of the male respondents 73% would like to take parental leave, 44% of all respondents (70% of the male respondents and 34% of the female respondents) agreed that radiology is more compatible with family than other medical disciplines and 87% would like to have a childcare possibility in close proximity to the working place. DISCUSSION/CONCLUSIONS: In most of the families the classic role model prevails, although women are well-educated and men also set a high value on the compatibility of family and profession and would like to take parental leave and work flexible working hours. This is a chance especially for radiology.

Height of Rectal Cancer: A Comparison between Rectoscopic and Different MRI Measurements.

PURPOSE: To compare rigid rectoscopy with three different MRI measurement techniques for rectal cancer height determination, all starting at the anal verge, in order to evaluate whether MRI measurements starting from the anal verge could be an alternative to rigid rectoscopy. Moreover, potential cut-off values for MRI in categorizing tumor height measurements were evaluated. METHODS: In this retrospective study, 106 patients (75 men, 31 female, mean age 64 ± 11.59 years) with primary rectal cancer underwent rigid rectoscopy as well as MR imaging. Three different measurements (MRI1-3) in T2w sagittal scans were used to evaluate the exact distance from the anal verge (AV) to the distal ending of the tumor (MRI1: two unbowed lines, AV to the upper ending of the anal canal and upper ending of the anal canal to the lower border of the tumor; MRI2: one straight line from the AV to the lower boarder of the tumor; MRI3: a curved line beginning at the AV and following the course of the rectum wall ending at the lower border of the tumor). Furthermore, agreement between the gold standard rigid rectoscopy (UICC classification: low part, 0-6 cm; mid part, 6-12 cm; and high part, >12 cm) and each MRI measuring technique was analyzed. RESULTS: Only a fair correlation in terms of individual measures between rectoscopy and all 3 MRI measurement techniques was shown. The proposed new cut-off values utilizing ROC analysis for the three different MRI beginning at the anal verge were low 0-7.7 cm, mid 7.7-13.3 cm, and high > 13.3 cm (MRI1); low 0-7.4 cm, mid 7.4-11.2 cm, and high > 11.2 cm (MRI2); and low 0-7.1 cm, mid 7.1-13.7 cm, and high > 13.7 cm (MRI3). For MRI1 and MRI3, the agreement to the gold standard was substantial (r = 0.66, r = 0.67, respectively). CONCLUSION: This study illustrates that MRI1 and MRI3 measures can be interchangeably used as a valid method to determine tumor height compared to the gold standard rigid rectoscopy.

Comparison of Modern 3D and 2D MR Imaging Sequences of the Wrist at 3 Tesla.

PURPOSE: To compare the image quality of modern 3 D and 2 D sequences for dedicated wrist imaging at 3 Tesla (T) MRI. MATERIALS AND METHODS: At 3 T MRI, 18 patients (mean age: 36.2 years) with wrist pain and 16 healthy volunteers (mean age: 26.4 years) were examined using 2 D proton density-weighted fat-saturated (PDfs), isotropic 3 D TrueFISP, 3 D MEDIC, and 3 D PDfs SPACE sequences. Image quality was rated on a five-point scale (0 - 4) including overall image quality (OIQ), visibility of important structures (cartilage, ligaments, TFCC) and degree of artifacts. Signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) of cartilage/bone/muscle/fluid as well as the mean overall SNR/CNR were calculated using region-of-interest analysis. ANOVA, paired t-, and Wilcoxon-signed-rank tests were applied. RESULTS: The image quality of all tested sequences was superior to 3 D PDfs SPACE (p < 0.01). 3 D TrueFISP had the highest combined cartilage score (mean: 3.4) and performed better in cartilage comparisons against 3 D PDfs SPACE in both groups and 2 D PDfs in volunteers (p < 0.05). 3 D MEDIC performed better in 7 of 8 comparisons (p < 0.05) regarding ligaments and TFCC. 2 D PDfs provided constantly high scores. The mean overall SNR/CNR for 2 D PDfs, 3 D PDfs SPACE, 3 D TrueFISP, and 3 D MEDIC were 68/65, 32/27, 45/47, and 57/45, respectively. 2 D PDfs performed best in most SNR/CNR comparisons (p < 0.05) and 3 D MEDIC performed best within the 3 D sequences (p < 0.05). CONCLUSION: Except 3 D PDfs SPACE, all tested 3 D and 2 D sequences provided high image quality. 3 D TrueFISP was best for cartilage imaging, 3 D MEDIC for ligaments and TFCC and 2 D PDfs for general wrist imaging. KEY POINTS: • 3 D TrueFISP is recommended for cartilage imaging of the wrist at 3 T.• 3 D MEDIC is recommended for ligaments and TFCC.• Robust 2 D PDfs should be used in routine protocols. 3 D sequences may be added depending on the clinical question.• 3 D PDfs SPACE is currently inferior. Citation Format: • Rehnitz C, Klaan B, von Stillfried F et al. Comparison of Modern 3D and 2D MR Imaging Sequences of the Wrist at 3 Tesla. Fortschr Röntgenstr 2016; 188: 753 - 762.

Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials.

Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression. Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55-0.75) and OS (HR 0.83; 95%-CI, 0.76-0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41-3.58). Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group.

PURPOSE: To evaluate whether cisplatin-based chemotherapy (gemcitabine, vinorelbine, and cisplatin [GVP]) prolongs overall survival in comparison to cisplatin-free chemotherapy (gemcitabine and vinorelbine [GV]) as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between September 1999 and June 2001, 300 patients with NSCLC stage IIIB with malignant pleural effusion or stage IV disease were randomly assigned to receive GV (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 every 3 weeks) or GVP (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 + cisplatin 75 mg/m(2) on day 2 every 3 weeks). Primary end point of the study was overall survival. RESULTS: Two hundred eighty-seven patients (GV, 143 patients; GVP, 144 patients) were eligible for analysis. At the time of analysis, April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287 patients had died (73%). No statistically significant difference was observed for overall survival (P =.73; median survival, 35.9 versus 32.4 weeks; 1-year survival rate, 33.6% versus 27.5%) as well as for event-free survival (P =.35; median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred fourteen patients were assessable for best response. The overall response rates were 13.0% for GV versus 28.3% for GVP (P =.004; complete responders, 0% versus 3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP. No statistically significant difference in quality of life was observed. CONCLUSION: In this phase III study, the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen, which was substantially better tolerated.

Radiation Dose Reduction in Digital Plain Radiography of the Knee after Total Knee Arthroplasty.

PURPOSE: To reduce radiation exposure of frequently performed radiographs of the knee in follow-up of total-knee arthroplasty ensuring accurate assessment by using objective quality control criteria. MATERIALS AND METHODS: In this prospective randomized study 278 radiographs of the knee in follow-up of total-knee arthroplasty were performed with standard and 37% reduced radiation dose. The evaluation of the plain-radiographs was conducted using the following criteria: bone-implant interface, implant-surface character, implant-implant discrimination and periarticular heterotopic ossification. Two radiologists evaluated these criteria using a score ranging from 1 (definitely assessable) to 4 (not assessable). If a single criterion had been evaluated with a score ≥ 3 or more than 2 criteria with ≥ 2 points, the radiograph was score das "not assessable". The study was designed as non-inferiority-trial. RESULTS: 100% of examined radiographs were scored as assessable, hence no statistical inferiority between the examinations with standard and reduced dose could be observed. Singular assessment of the defined criteria was likewise dose-independent. CONCLUSION: Plain-radiography of the knee following total-knee arthroplasty can be performed with 63% of standard dose without loss of diagnostic validity. KEY POINTS: Due to the non-inferiority of digital radiographs of the knee joint after total-knee arthroplasty done with 37% reduced image receiver dose we recommend the tested speed class of SC 800 as a new reference value for digital radiographs with this indication.

A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS: The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.

[Modern digital plain-radiography of the whole spine in scoliosis patients--dose reduction and quality criteria]. / Moderne digitale Radiografie der Ganzwirbelsäule bei Skoliose - Dosisreduktion und Qualitätskriterien.

PURPOSE: To reduce the radiation exposure of plain radiographs of the entire spine depending on specific indications, since these are frequently performed examinations of children and young adults with scoliosis and to determine objective quality control criteria to ensure accurate assessment. MATERIALS AND METHODS: In this prospective randomized study 323 patients underwent plain-radiography of the entire spine with standard and 50 % reduced dose. In an experimental pilot-study this target-dose was determined using an Alderson-Phantom. The evaluation of the experimental radiographs, as well as, the randomized plain-radiographs was conducted using the following criteria: endplates (Cobb-angle), spinal process and pedicel (rotation), lateral margin of the vertebral body (lateral alignment), identification of C7 / S1 (perpendicular). Two radiologists evaluated these criteria using a score ranging from 1 (definitely assessable) to 4 (not assessable). If one single criteria was evaluated with a score of 3 or more points or more than 2 criteria with 2 points, the radiograph was scored as "not assessable". The statistical analysis was conducted as a non-inferiority-trial. RESULTS: Seven (2.4 %) of the 290 examined x-rays were scored as not assessable. There was no statistic inferiority between the examinations with standard or reduced dose, while singular assessment of the defined criteria was likewise dose-independent. CONCLUSION: Plain-radiography of the total spine in patients with scoliosis can be performed with a dose reduction of 50% without a loss of validity. The obtained quality control criteria were clinically applicable.

A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV.

Sorafenib is a multi-kinase inhibitor with antiangiogenic and antiproliferative activity. The activity of sorafenib in progressive hormone-refractory prostate cancer (HRPC) patients was investigated in a phase II clinical study. Progressive HRPC patients received sorafenib 400 mg bid p.o. continuously. Only patients with no prior chemotherapy, and either one-unidimensional measurable lesion according to RECIST-criteria or increasing prostate-specific antigen (PSA) values reflecting a hormone-refractory situation, were eligible for study entry. The primary study objective was the rate of progression-free survival of >/=12 weeks (PFS12). Secondary end points were overall response, overall survival, and toxicity. Fifty-seven patients with PC were enrolled. Two patients had to be withdrawn from the set of eligible patients. According to RECIST criteria, 4 patients out of 55 evaluable patients showed stable disease (SD). According to PSA-response, we saw 11 patients with SD PSA and 2 patients were responders at 12 weeks (PFS12=17/55=31%). Among the 257 adverse events, 15 were considered drug related of maximum CTC-grade 3. Twenty-four serious adverse events occurred in 14 patients (14/55=26%). Seven of them were determined to be drug related. No treatment-related death was observed. Sorafenib has antitumour activity in HRPCP when evaluated for RECIST- and PSA-based response. Further investigation as a component of combination regimens is necessary to evaluate its definite or overall clinical benefit for HRPCP.